ClinVar Miner

Submissions for variant NM_002834.5(PTPN11):c.836A>G (p.Tyr279Cys) (rs121918456)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 23
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030620 SCV000053298 pathogenic Noonan syndrome with multiple lentigines 2019-04-22 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.836A>G (p.Tyr279Cys) results in a non-conservative amino acid change located in the Tyrosine specific protein phosphatases domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245584 control chromosomes (gnomAD). c.836A>G has been reported in the literature in multiple individuals affected with Noonan Syndrome/Leopard Syndrome (Keren_2004, Harakmi_2016). These data indicate that the variant is very likely to be associated with disease. Multiple functional studies have indicated the variant abolishes enzymatic activity of PTPN11 and increases AKT, the variant's mechanism causes a gain of function (Yu_2014). The variant has been established to be a common disease variant by multiple publications. In addition, nine ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx RCV000077859 SCV000057409 pathogenic not provided 2021-03-09 criteria provided, single submitter clinical testing Published functional studies demonstrate weakened interactions between the N-SH2 and PTP domains leading to sustained RAS-ERK1/2 activation (Yu et al., 2014; Kontaridis et al., 2006); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 32164556, 31722741, 31560489, 29907801, 31446693, 30050098, 26918529, 30417923, 30692697, 30732632, 19520282, 16679933, 16172598, 12058348, 23673659, 23457302, 21339643, 20493809, 28483241, 19725129, 19768645, 26377839, 25917897, 22822385, 24803665, 14991917, 24401936, 24037001, 24935154, 18849586, 18372317, 16638574, 16377799, 23312806, 24628801, 24820750, 20308328, 24775816, 24034393, 16358218, 15520399, 15121796, 12161596, 11992261, 26337637)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000077859 SCV000058294 pathogenic not provided 2013-03-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000824744 SCV000200016 pathogenic Noonan syndrome with multiple lentigines; Noonan syndrome 2013-04-09 criteria provided, single submitter clinical testing The p.Tyr279Cys variant in PTPN11 has previously been reported in several indivi duals with clinical features of Noonan or LEOPARD syndrome, segregated with dis ease in multiple families, and occured as a de novo variant in sporadic cases (F roster 2003, Tartaglia 2006, Martinelli 2008, Tang 2009, Digilio 2002, Kalev 200 9, Legius 2002, Legius 2002, Oishi 2009). It was absent from large population st udies. In summary, this variant meets our criteria to be classified as pathogeni c for Noonan syndrome and LEOPARD syndrome in an autosomal dominant manner (http ://www.partners.org/personalizedmedicine/LMM).
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000055890 SCV000268512 pathogenic LEOPARD syndrome 1 2016-03-17 criteria provided, single submitter clinical testing This de novo mutation identified in the PTPN11 gene is one of the well-described mutations causing the LEOPARD syndrome.
Invitae RCV000033504 SCV000287695 pathogenic Rasopathy 2020-09-09 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 279 of the PTPN11 protein (p.Tyr279Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with Noonan syndrome with multiple lentigines (NSML; also known as LEOPARD syndrome) in a single family (PMID: 24401936) and has also been reported in many unrelated individuals with NSML (PMID: 25917897, 24820750, 22822385, 15520399, 17020470, 22681964). ClinVar contains an entry for this variant (Variation ID: 13328). Experimental studies have shown that this missense change abolishes the enzymatic activity of PTPN11 in vitro and increases the activity of AKT and mTOR in cell culture (PMID: 16377799, 16638574, 23673659, 18372317, 21339643). For these reasons, this variant has been classified as Pathogenic.
Institute of Molecular Biology and Genetics, Federal Almazov North-West Medical Research Centre RCV000492270 SCV000494671 pathogenic Noonan syndrome-like disorder with or without juvenile myelomonocytic leukemia 2014-12-30 criteria provided, single submitter research The variant was detected in a neonate with congenital intrauterine revealed myocardial hypertrophy. The main clinical sign was myocardial hypertrophy and cardiac output deficit due to reduced LV cavity. No morphological signs of Noonan syndrome were observed. The variant was detected in combination with CBL NM_005188: exon11: c.G1754T :p.R585L variant in RAS-pathway (PMID 25731833).
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine RCV000577894 SCV000583577 likely pathogenic Noonan syndrome 1 2017-06-01 criteria provided, single submitter research
Ambry Genetics RCV000617951 SCV000739978 pathogenic Cardiovascular phenotype 2018-03-06 criteria provided, single submitter clinical testing The p.Y279C pathogenic mutation (also known as c.836A>G), located in coding exon 7 of the PTPN11 gene, results from an A to G substitution at nucleotide position 836. The tyrosine at codon 279 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation has been reported in multiple patients and families with a clinical diagnosis of Noonan syndrome or related disorder, most of whom had skin findings including multiple lentigines and/or cafe-au-lait spots, and several patients had hypertrophic cardiomyopathy or other cardiac findings (Tartaglia M, Am. J. Hum. Genet. 2002 Jun; 70(6):1555-63; Keren B, J. Med. Genet. 2004 Nov; 41(11):e117; Carcavilla A, Rev Esp Cardiol (Engl Ed) 2013 May; 66(5):350-6; Conboy E et al. J Med Genet. 2016;53(2):123-6). One study reported this mutation had occurred de novo in the index case, and co-segregated with disease in four affected offspring (Begić F, Eur. J. Pediatr. 2014 Jun; 173(6):819-22). The p.Y279C mutation is one of the most common mutations reported in Noonan syndrome and related disorders, it is in the protein tyrosine phosphatase (PTP) functional domain, and another pathogenic variant at the same codon, p.Y279S, has been reported in affected individuals (Tartaglia M, Eur J Med Genet. 2005 Apr; 48(2):81-96). In addition, a functional study of fibroblasts from individuals heterozygotes for this mutation, and HEK293 cells transfected with this mutation, showed significantly stronger EGF-induced phosphorylation of downstream targets when compared to normal controls (Edouard T, Mol. Cell. Biol. 2010 May; 30(10):2498-507). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000055890 SCV000782250 pathogenic LEOPARD syndrome 1 2016-11-01 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768062 SCV000898916 pathogenic Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 2018-07-18 criteria provided, single submitter clinical testing PTPN11 NM_002834.4 exon 7 p.Tyr279Cys (c.836A>G): This variant is a well established and commonly reported pathogenic variant in the literature, identified in several individuals with Noonan syndrome/LEOPARD syndrome, including a GeneReviews entry. This variant has been published as segregating with disease in multiple affected family members, and as a de novo occurence (Legius 2002 PMID:12161596, Tartaglia 2002 PMID:11992261, Kalev 2010 PMID:19768645, Begic 2014 PMID:24401936, Gelb 2015 PMID:20301557). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:13328). Evolutionary conservation and computational predictive tools support that this variant may impact the protein. In addition, functional studies (including a drosophila model) have shown a deleterious effect of this variant (Kontaridis 2006 PMID: 16377799, Martinelli 2008 PMID:18372317, Oishi 2009 PMID:18849586). In summary, this variant is classified as pathogenic.
Blueprint Genetics RCV000077859 SCV000927420 pathogenic not provided 2017-10-03 criteria provided, single submitter clinical testing
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery,Institute of Otolaryngology, Chinese PLA General Hospital RCV000055890 SCV000992399 pathogenic LEOPARD syndrome 1 criteria provided, single submitter case-control
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000775 SCV001157828 pathogenic not specified 2018-09-09 criteria provided, single submitter clinical testing The PTPN11 c.836A>G; p.Tyr279Cys variant (rs121918456) is reported in the literature in numerous individuals affected with Noonan syndrome and LEOPARD syndrome, also known as Noonan syndrome with multiple lentigines (Begic 2014, Digilio 2004, Legius 2002, Quaio 2013, Sarkozy 2004, Tartaglia 2002, Wang 2014). This is a recurrent variant reported to cosegregate with disease in families (Begic 2014, Legius 2002) and also observed de novo (Begic 2014, Digilio 2004, Wang 2014). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 13328), and it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The tyrosine at codon 279 is highly conserved and interacts with an active site loop required for catalysis (Kontaridis 2006, Qiu 2014), and biochemical analyses demonstrate strongly reduced phosphatase activity of the p.Tyr279Cys variant (Hanna 2006, Qiu 2014). In both cultured cells and mice, the p.Tyr279Cys variant exhibits a dominant negative effect on Erk/MAPK signaling (Kontaridis 2006, Marin 2011), and the mouse model of PTPN11 p.Tyr279Cys recapitulates physiological symptoms of human LEOPARD syndrome, including skeletal abnormalities and hypertrophic cardiomyopathy (Marin 2011). Additionally, another variant at this codon (p.Tyr279Ser) has been reported in an individual with symptoms of LEOPARD syndrome (Sarkozy 2004), reiterating its functional importance. Based on available information, the p.Tyr279Cys variant is considered to be pathogenic. References: Begic F et al. Leopard syndrome: a report of five cases from one family in two generations. Eur J Pediatr. 2014 Jun;173(6):819-22. Digilio MC et al. Familial aggregation of genetically heterogeneous hypertrophic cardiomyopathy: a boy with LEOPARD syndrome due to PTPN11 mutation and his nonsyndromic father lacking PTPN11 mutations. Birth Defects Res A Clin Mol Teratol. 2004 Feb;70(2):95-8. Hanna N et al. Reduced phosphatase activity of SHP-2 in LEOPARD syndrome: consequences for PI3K binding on Gab1. FEBS Lett. 2006 May 1;580(10):2477-82. Kontaridis MI et al. PTPN11 (Shp2) mutations in LEOPARD syndrome have dominant negative, not activating, effects. J Biol Chem. 2006 Mar 10;281(10):6785-92. Legius E et al. PTPN11 mutations in LEOPARD syndrome. J Med Genet. 2002 Aug;39(8):571-4. Marin TM et al. Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J Clin Invest. 2011 Mar;121(3):1026-43. Qiu W et al. Structural insights into Noonan/LEOPARD syndrome-related mutants of protein-tyrosine phosphatase SHP2 (PTPN11). BMC Struct Biol. 2014 Mar 14;14:10. Quaio CR et al. Tegumentary manifestations of Noonan and Noonan-related syndromes. Clinics (Sao Paulo). 2013;68(8):1079-83. Sarkozy A et al. Clinical and molecular analysis of 30 patients with multiple lentigines LEOPARD syndrome. J Med Genet. 2004 May;41(5):e68. Tartaglia M et al. PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet. 2002 Jun;70(6):1555-63. Wang Y et al. Leopard syndrome caused by heterozygous missense mutation of Tyr 279 Cys in the PTPN11 gene in a sporadic case of Chinese Han. Int J Cardiol. 2014 Jul 1;174(3):e101-4.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000077859 SCV001246730 pathogenic not provided 2017-08-01 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000055890 SCV001368894 pathogenic LEOPARD syndrome 1 2019-02-25 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PM5,PP2,PP3.
OMIM RCV000055890 SCV000034504 pathogenic LEOPARD syndrome 1 2010-05-01 no assertion criteria provided literature only
GeneReviews RCV000055890 SCV000086896 pathologic LEOPARD syndrome 1 2010-11-16 no assertion criteria provided curation Converted during submission to Pathogenic.
Baylor Genetics RCV000033504 SCV000196665 pathogenic Rasopathy no assertion criteria provided clinical testing Variant classified using ACMG guidelines
Institute of Human Genetics, Klinikum rechts der Isar RCV000577894 SCV000680351 pathogenic Noonan syndrome 1 2017-12-18 no assertion criteria provided clinical testing
Baylor Genetics RCV000577894 SCV000854622 pathogenic Noonan syndrome 1 2018-11-18 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000077859 SCV001799797 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000077859 SCV001955959 pathogenic not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.